Recent studies have demonstrated that Olfactory Receptors (ORs) play important physiological roles as chemosensors in tissues beyond the nose. We have reported that one of the ORs expressed in the kidney, Olfactory Receptor 78 (Olfr78), plays an important role in blood pressure (BP) regulation. Intriguingly, the ligands for this receptor are short chain fatty acids (SCFAs), which are metabolites produced by the gut microbiota. The key role of Olfr78 in modulating BP is clearly demonstrated by the hypotension (~13mmHg) observed in mice null for Olfr78 (Olfr78 KO). However, Olfr78 localizes to multiple tissues that influence BP regulation - it is not only found in the renal juxtaglomerular apparatus (JGA), which plays a role in renin secretion, but it is also expressed in the peripheral vasculature, where it appears to modulate vascular tone. In this proposal, we will utilize the flox cre system to determine which site of Olfr78 expression is the primary contributor to the hypotension seen in the KO mice (SA1). In addition, because Olfr78 KO mice are hypotensive, we hypothesize that an Olfr78 antagonist would likewise lower BP and would be an extremely useful tool for teasing apart the role of Olfr78 in BP regulation in vivo. Therefore, in SA2, we wil carry out in vitro studies to characterize Olfr78 antagonists (building upon our strong preliminary data), and will determine which compounds are the best candidates for in vivo use. In SA3, we will utilize Olfr78 antagonists in vivo in both wild-type and various KO mice in order to advance our understanding of Olfr78 function. In sum, our data implies that a novel renal OR plays a role in modulating BP regulation in response to changes in gut microbial metabolism. The proposed work invokes a variety of in vitro and in vivo techniques in order to advance our understanding of BP regulation by studying an entirely novel pathway involving a novel renal OR. These studies have the potential to lead to potentially exciting future clinical implications, as our dat suggests that manipulating Olfr78 in vivo has the potential to significantly alter BP.